tbuckley/cabot-search huggingface dataset:
A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease
Authors: Peng Zhao, Yuanzhong Xu, LuLin Jiang, Xuejun Fan, Leike Li, Xin Li, Hisashi Arase, Yingjun Zhao, Wei Cao, Hui Zheng, Huaxi Xu, Qingchun Tong, Ningyan Zhang, Zhiqiang An
Journal: Science Translational Medicine (2022)

Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in Alzheimer's disease (AD) by regulating microglia migration toward, and phagocytosis of oligomeric amyloid-β (oAβ) and amyloid plaques. Studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library. By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold. Stronger TREM2 activation led to enhanced microglia phagocytosis of the oAβ-lipid complex, migration toward oAβ, and improved microglia survival in vitro. Mechanistic studies showed increased TREM2 clustering on microglia by the tetravalent Ab18 TVD-Ig without altering microglial TREM2 amount. An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/αTfR) improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/αTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining. This study demonstrated the feasibility of engineering multivalent TREM2 agonistic Ab coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo. This Ab engineering approach enables the development of effective TREM2-targeting therapies for AD.
Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection
Authors: Kevin O. Saunders, Robert J. Edwards, Kedamawit Tilahun, Kartik Manne, Xiaozhi Lu, Derek W. Cain, Kevin Wiehe, Wilton B. Williams, Katayoun Mansouri, Giovanna E. Hernandez, Laura Sutherland, Richard Scearce, Robert Parks, Maggie Barr, Todd DeMarco, Chloe M. Eater, Amanda Eaton, Georgeanna Morton, Benjamin Mildenberg, Yunfei Wang, R. Wes Rountree, Mark A. Tomai, Christopher B. Fox, M. Anthony Moody, S. Munir Alam, Sampa Santra, Mark G. Lewis, Thomas N. Denny, George M. Shaw, David C. Montefiori, Priyamvada Acharya, Barton F. Haynes
Journal: Science Translational Medicine (2022)

A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID 50 titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4 + T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine–induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env.
Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation
Authors: Girieca Lorusso, Christof B. Wyss, François Kuonen, Nicola Vannini, Clotilde Billottet, Nathalie Duffey, Raphael Pineau, Qiang Lan, Pratyaksha Wirapati, David Barras, Alessandro Tancredi, Ruth Lyck, Hans-Anton Lehr, Britta Engelhardt, Mauro Delorenzi, Andreas Bikfalvi, Curzio Rüegg
Journal: Science Translational Medicine (2022)

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM 2 ) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM 2 model and in human MDA231-BrM 2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin–mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM 2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK–NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.
Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy
Authors: Ziyue Gu, Yanli Yao, Guizhu Yang, Guopei Zhu, Zhen Tian, Rui Wang, Qi Wu, Yujue Wang, Yaping Wu, Lan Chen, Chong Wang, Jiamin Gao, Xindan Kang, Jie Zhang, Lizhen Wang, Shengzhong Duan, Zhongming Zhao, Zhiyuan Zhang, Shuyang Sun
Journal: Science Translational Medicine (2022)

Head and neck squamous cell carcinoma (HNSCC) is a common and frequently lethal cancer with few therapeutic options. In particular, there are few effective targeted therapies. Development of highly effective therapeutic strategies tailored to patients with HNSCC remains a pressing challenge. To address this, we present a pharmacogenomic study to facilitate precision treatments for patients with HNSCC. We established a large collection of 56 HNSCC patient-derived cells (PDCs), which recapitulated the molecular features of the original tumors. Pharmacological assessment of HNSCCs was conducted using a three-tiered high-throughput drug screening using 2248 compounds across these PDC models and an additional 18 immortalized cell lines. We integrated genomic, transcriptomic, and pharmacological analysis to predict biomarkers, gene-drug associations, and validated biomarkers. These results supported drug repurposing for multiple HNSCC subtypes, including the JAK2 inhibitor fedratinib, for low KRT18-expressing HNSCC cases, and the topoisomerase inhibitor mitoxantrone, for IL6R-activated HNSCC cases. Our results demonstrated concordance between susceptibility predictions from the PDCs and the matched patients' responses to standard clinical medication. Moreover, we identified and experimentally confirmed that high expression of ITGB1 elicited therapeutic resistance to docetaxel and high SOD1 expression conferred resistance to afatinib. We further validated ITGB1 as a predictive biomarker for the efficacy of docetaxel therapy in a phase 2 clinical trial. In summary, our study shows that this HNSCC cell resource, as well as the resulting pharmacogenomic profiles, is effective for biomarker discovery and for guiding precision oncology therapies in HNSCCs.
Glucose/Fructose Delivery to the Distal Nephron Activates the Sodium-Chloride Cotransporter via the Calcium-Sensing Receptor
Authors: Jessica Paola Bahena-Lopez, Lorena Rojas-Vega, María Chávez-Canales, Silvana Bazua-Valenti, Rocío Bautista-Pérez, Ju-Hye Lee, Magdalena Madero, Natalia Vazquez-Manjarrez, Ivan Alquisiras-Burgos, Arturo Hernandez-Cruz, María Castañeda-Bueno, David H. Ellison, Gerardo Gamba
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement The calcium-sensing receptor (CaSR) activates salt reabsorption through the sodium-chloride cotransporter (NCC) via the WNK4-SPAK pathway. Glucose and other sugars are positive allosteric modulators of the CaSR. This would be irrelevant for most cells that come into contact with glucose, except for the nephron segments beyond the proximal tubule. Using in vitro and in vivo models, this work shows that the arrival of glucose or fructose to the distal nephron modulates the CaSR due to a positive allosteric type II effect associated with activation of the WNK4-SPAK-NCC pathway. This study proposes a mechanism by which glucose or fructose delivered to the distal nephron contributes to renal salt retention by their allosteric effect on the CaSR. Background The calcium-sensing receptor (CaSR) in the distal convoluted tubule (DCT) activates the NaCl cotransporter (NCC). Glucose acts as a positive allosteric modulator of the CaSR. Under physiologic conditions, no glucose is delivered to the DCT, and fructose delivery depends on consumption. We hypothesized that glucose/fructose delivery to the DCT modulates the CaSR in a positive allosteric way, activating the WNK4-SPAK-NCC pathway and thus increasing salt retention. Methods We evaluated the effect of glucose/fructose arrival to the distal nephron on the CaSR-WNK4-SPAK-NCC pathway using HEK-293 cells, C57BL/6 and WNK4-knockout mice, ex vivo perfused kidneys, and healthy humans. Results HEK-293 cells exposed to glucose/fructose increased SPAK phosphorylation in a WNK4- and CaSR-dependent manner. C57BL/6 mice exposed to fructose or a single dose of dapagliflozin to induce transient glycosuria showed increased activity of the WNK4-SPAK-NCC pathway. The calcilytic NPS2143 ameliorated this effect, which was not observed in WNK4-KO mice. C57BL/6 mice treated with fructose or dapagliflozin showed markedly increased natriuresis after thiazide challenge. Ex vivo rat kidney perfused with glucose above the physiologic threshold levels for proximal reabsorption showed increased NCC and SPAK phosphorylation. NPS2143 prevented this effect. In healthy volunteers, cinacalcet administration, fructose intake, or a single dose of dapagliflozin increased SPAK and NCC phosphorylation in urinary extracellular vesicles. Conclusions Glycosuria or fructosuria was associated with increased NCC, SPAK, and WNK4 phosphorylation in a CaSR-dependent manner.
Eprenetapopt in the Post-Transplant Setting: Mechanisms and Future Directions
Authors: Abhishek Maiti, Naval G. Daver
Journal: Journal of Clinical Oncology (2022)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. July 11, 2022 ARTICLE CITATION DOI: 10.1200/JCO.22.01505 Journal of Clinical Oncology - published online before print September 7, 2022 PMID: 36070541 Eprenetapopt in the Post-Transplant Setting: Mechanisms and Future Directions Abhishek Maiti , MBBS1xAbhishek MaitiSearch for articles by this author; and Naval G. Daver , MD1xNaval G. DaverSearch for articles by this author Show More 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.22.01505 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologySUPPORTSupported in part by the MD Anderson Cancer Center Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif. Souki Cancer Research Fund, and generous philanthropic contributions to the MD Anderson Moon Shots Program.AUTHOR CONTRIBUTIONSConception and design: All authorsCollection and assembly of data: All authorsData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTEprenetapopt in the Post-Transplant Setting: Mechanisms and Future DirectionsThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Abhishek MaitiResearch Funding: Celgene (Inst)Naval G. DaverConsulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics, Gilead Sciences, Arog, Shattuck LabsResearch Funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, AbbVie, Astellas Pharma, Sevier, Daiichi Sankyo, Gilead Sciences, Amgen, Trillium Therapeutics, Hanmi, Trovagene, FATE Therapeutics, Novimmune, GlycoMimeticsNo other potential conflicts of interest were reported. Companion Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes
Data-Driven Chronic Allograft Phenotypes: A Novel and Validated Complement for Histologic Assessment of Kidney Transplant Biopsies
Authors: Thibaut Vaulet, Gillian Divard, Olivier Thaunat, Priyanka Koshy, Evelyne Lerut, Aleksandar Senev, Olivier Aubert, Elisabet Van Loon, Jasper Callemeyn, Marie-Paule Emonds, Amaryllis Van Craenenbroeck, Katrien De Vusser, Ben Sprangers, Maud Rabeyrin, Valérie Dubois, Dirk Kuypers, Maarten De Vos, Alexandre Loupy, Bart De Moor, Maarten Naesens
Journal: Journal of the American Society of Nephrology (2022)

No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity.The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval.We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P<0.001), independent of the total activity scores (HR, 5.01; 95% CI, 2.83 to 7.00; P<0.001). These results were validated on an external cohort of 4031 biopsies from 2054 kidney transplant recipients.The evaluation of total chronicity provides information on kidney transplant pathology that complements the estimation of disease activity from acute lesion scores. Use of the data-driven algorithm used in this study, called RejectClass, may provide a holistic and quantitative assessment of kidney transplant injury phenotypes and severity.
Safety, Immunogenicity, and 1-Year Efficacy of Universal Cancer Peptide–Based Vaccine in Patients With Refractory Advanced Non–Small-Cell Lung Cancer: A Phase Ib/Phase IIa De-Escalation Study
Authors: Olivier Adotévi, Dewi Vernerey, Pascale Jacoulet, Aurélia Meurisse, Caroline Laheurte, Hamadi Almotlak, Marion Jacquin, Vincent Kaulek, Laura Boullerot, Marine Malfroy, Emeline Orillard, Guillaume Eberst, Aurélie Lagrange, Laure Favier, Marie Gainet-Brun, Ludovic Doucet, Luis Teixeira, Zineb Ghrieb, Anne-Laure Clairet, Yves Guillaume, Marie Kroemer, Didier Hocquet, Mélanie Moltenis, Samuel Limat, Elisabeth Quoix, Céline Mascaux, Didier Debieuvre, Christine Fagnoni-Legat, Christophe Borg, Virginie Westeel
Journal: Journal of Clinical Oncology (2022)

Universal cancer peptide-based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non-small-cell lung cancer (NSCLC).Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year.A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders (P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders (P = .005), respectively.UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.
A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor–Positive Ovarian Cancer (Study 006)
Authors: Janos L. Tanyi, Leslie M. Randall, Setsuko K. Chambers, Kristina A. Butler, Ira S. Winer, Carrie L. Langstraat, Ernest S. Han, Alexander L. Vahrmeijer, Hye Sook Chon, Mark A. Morgan, Matthew A. Powell, Jill H. Tseng, Alexis S. Lopez, Robert M. Wenham
Journal: Journal of Clinical Oncology (2022)

PURPOSE The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer. METHODS This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P &lt; .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P &lt; .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.
Trends in Heart Failure–Related Mortality Among Older Adults in the United States From 1999-2019
Authors: Tariq Jamal Siddiqi, Abdul Mannan Khan Minhas, Stephen J. Greene, Harriette G.C. Van Spall, Sadiya S. Khan, Ambarish Pandey, Robert J. Mentz, Gregg C. Fonarow, Javed Butler, Muhammad Shahzeb Khan
Journal: JACC Heart Failure (2022)
Acute Myocarditis Associated With Desmosomal Gene Variants
Authors: Enrico Ammirati, Francesca Raimondi, Nicolas Piriou, Loren Sardo Infirri, Saidi A. Mohiddin, Andrea Mazzanti, Chetan Shenoy, Ugo A. Cavallari, Massimo Imazio, Giovanni Donato Aquaro, Iacopo Olivotto, Patrizia Pedrotti, Neha Sekhri, Caroline M. Van de Heyning, Glenn Broeckx, Giovanni Peretto, Oliver Guttmann, Santo Dellegrottaglie, Alessandra Scatteia, Piero Gentile, Marco Merlo, Randal I. Goldberg, Alex Reyentovich, Christopher Sciamanna, Sabine Klaassen, Wolfgang Poller, Cory R. Trankle, Antonio Abbate, Andre Keren, Smadar Horowitz-Cederboim, Julia Cadrin-Tourigny, Rafik Tadros, Giuseppe A. Annoni, Emanuela Bonoldi, Claire Toquet, Lara Marteau, Vincent Probst, Jean Noël Trochu, Antheia Kissopoulou, Aurelia Grosu, Deni Kukavica, Alessandro Trancuccio, Cristina Gil, Giacomo Tini, Matteo Pedrazzini, Margherita Torchio, Gianfranco Sinagra, Juan Ramón Gimeno, Davide Bernasconi, Maria Grazia Valsecchi, Karin Klingel, Eric D. Adler, Paolo G. Camici, Leslie T. Cooper
Journal: JACC Heart Failure (2022)